This invention is directed to substituted pyrrolidines, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cellxe2x80x94cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. xcex15xcex21 (VLA-5), xcex14xcex21 (VLA-4) and xcex1Vxcex23]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflanimation, atherosclerosis and autoimniune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called xcex1 and xcex2. There are at least fifteen different xcex1-subunits (xcex11-xcex19, xcex1-L, xcex1-M, xcex1-X, xcex1-IIb, xcex1-V and xcex1-E) and at least seven different xcex2(xcex21-xcex27) subunits. The integrin family can be subdivided into classes based on the xcex2 subunits, which can be associated with one or more xcex1-subunits. The most widely distributed integrins belong to the xcex21 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three xcex1-subunits (xcex1-L, xcex1-M or xcex1-X) complexed with the xcex22 protein. The cytoadhesins xcex1-IIbxcex23 and xcex1-Vxcex23, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor xcex14xcex21 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin xcex14xcex21 mediates both cellxe2x80x94cell and cell-matrix interactions. Cells expressing xcex14xcex21 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-xcex3, TNF-xcex1, IL-1⊕ and IL-4.
Regulation of xcex14xcex21 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which xcex14xcex21 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflanimation (S. M. Wahl et al., J. Clin. Invest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-xcex14 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1/2, an anti-xcex14 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W. M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).
We have now found a novel group of substituted pyrrolidines which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 ((xcex14xcex21).
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein:
one of A1, A2 and A3 represents NR2 and the others represent C(R3)(R4);
R1 represents R5Z1xe2x80x94Hetxe2x80x94 or R6N(R7)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar2xe2x80x94
R2 represents xe2x80x94C(xe2x95x90O)xe2x80x94R8, xe2x80x94C(xe2x95x90O)xe2x80x94OR8a or R8b;
R3 and R4 each represent hydrogen or R8;
R5 represents aryl; heteroaryl; alkyl, alkenyl or alkynyl, each optionally substituted by R9, xe2x80x94Z2R10, xe2x80x94Z3H, xe2x80x94C(xe2x95x90O)xe2x80x94R10, xe2x80x94NR11xe2x80x94C(xe2x95x90Z3)xe2x80x94R11, xe2x80x94NR11xe2x80x94C(xe2x95x90O)xe2x80x94OR10, xe2x80x94NR11xe2x80x94SO2xe2x80x94R10, xe2x80x94SO2xe2x80x94NY1Y2, xe2x80x94NY1Y2 or xe2x80x94C(xe2x95x90Z3)xe2x80x94NY1Y2; or cycloalkyl or heterocycloalkyl, each optionally substituted by R10, xe2x80x94Z2R10, xe2x80x94Z3H, xe2x80x94C(xe2x95x90O)xe2x80x94R10, xe2x80x94NR11xe2x80x94C(xe2x95x90Z3)xe2x80x94R10, xe2x80x94NR11xe2x80x94C(xe2x95x90O)xe2x80x94OR10, xe2x80x94NR11xe2x80x94SO2xe2x80x94R10, xe2x80x94SO2-NY1Y2, xe2x80x94NY1Y2 or xe2x80x94C(xe2x95x90Z3)xe2x80x94NY1Y2;
R6 represents hydrogen or lower alkyl and R7 represents aryl, arylalkyl, heteroaryl or heteroarylalkyl; or
R6 and R7 together with the nitrogen atom to which they are attached form a cyclic amine;
R8 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or alkyl substituted by an acidic functional group or corresponding protected derivative, or by xe2x80x94Z3H, xe2x80x94Z2R10, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 or xe2x80x94NY1Y2;
R8a represents alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R8b represents alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkyl substituted by an acidic functional group or corresponding protected derivative;
R9 represents aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycloalkyl;
R10 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
R11 represents hydrogen or lower alkyl;
R12 is a direct bond or an alkylene chain, an alkenylene chain or an alkynylene chain;
R13 is a direct bond, cycloalkylene, heterocycloalkylene, aryldiyl, heteroaryldiyl, xe2x80x94C(xe2x95x90Z3)xe2x80x94NR11xe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90Z3)xe2x80x94, xe2x80x94Z3xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR11), xe2x80x94NR11xe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90Z3)xe2x80x94NR11, xe2x80x94SO2xe2x80x94NR11xe2x80x94, xe2x80x94NR11xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NR11xe2x80x94;
Ar1 represents aryldiyl or heteroaryldiyl;
Ar2 represents aryldiyl or heteroaryldiyl;
Het represents a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N, optionally substituted by one or more aryl group substituents;
L1 represents a xe2x80x94R12xe2x80x94R13xe2x80x94 linkage;
Y is carboxy or an acid bioisostere;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group xe2x80x94NY1Y2 may form a cyclic amine;
Z1 represents NH;
Z2 is O or S(O)n;
Z3 is O or S;
n is zero or an integer 1 or 2;
(but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond of an alkenyl or alkynyl residue);
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993,33,p576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995,p34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995,343,p105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcidic functional groupxe2x80x9d means a group with an acidic hydrogen within it. The xe2x80x9ccorresponding protected derivativesxe2x80x9d are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-benzyl derivatives of imidazoles.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkylxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbonxe2x80x94carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched C2-6alkenyl group. Exemplary alkenylene radicals include vinylene and propylene.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched C1-6alkyl group. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
xe2x80x9cAlkylenedioxyxe2x80x9d means an xe2x80x94O-alkyl-Oxe2x80x94 group in which the alkyl group is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbonxe2x80x94carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAlkynylenexe2x80x9d means an aliphatic bivalent radical derived from a C2-6alkynyl group. Exemplary alkenylene radicals include ethynylene and propynylene.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y1Y2Nxe2x80x94, Y1Y2NCOxe2x80x94, Y1Y2NSO2xe2x80x94, Y1Y2Nxe2x80x94C2-6alkylene-Zxe2x80x94 [where Z is O, NR11 or S(O)n], alkylC(xe2x95x90O)xe2x80x94Y1Nxe2x80x94, alkylSO2xe2x80x94Y1Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or
Y1Y2Nxe2x80x94. When R5 is an optionally substituted aryl group, this may particularly represent optionally substituted phenyl.
xe2x80x9cArylalkenylxe2x80x9d means an aryl-alkenyl-group in which the aryl and alkenyl moieties are as previously described.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl-group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cArylalkynylxe2x80x9d means an aryl-alkynyl-group in which the aryl and alkynyl moieties are as previously described.
xe2x80x9cAryldiylxe2x80x9d means an optionally substituted bivalent radical derived from an aryl group. Exemplary aryldiyl groups include optionally substituted phenylene, naphthylene and indanylene. Suitable substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, particularly halogen, methyl or methoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, oxazolyl and benzimidazolyl.
xe2x80x9cAzaheteroaryldiylxe2x80x9d means a bivalent radical derived from an azaheteroaryl group.
xe2x80x9cCyclic aminexe2x80x9d means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof) or R8; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY3 (where Y3 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94C(xe2x95x90O)xe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94OR14 or xe2x80x94SO2R14 and R14 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl); and (iii) may be fused to additional aryl (e.g. phenyl), heteroaryl (e.g. pyridyl), heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinolinyl and the like groups. When the group R6N(R7)xe2x80x94 is a cyclic amine this may particularly represent indolinyl or tetrahydroquinolinyl.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbonxe2x80x94carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
xe2x80x9cCycloalkenylalkylxe2x80x9d means a cycloalkenyl-alkyl-group in which the cycloalkenyl and alkyl moieties are as previously described.
xe2x80x9cCycloalkylalkenylxe2x80x9d means a cycloalkyl-alkenyl-group in which the cycloalkyl and alkenyl moieties are as previously described.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkylalkenylxe2x80x9d means a cycloalkyl-alkenyl-group in which the cycloalkyl and alkenyl moieties are as previously described.
xe2x80x9cCycloalkylalkyflylxe2x80x9d means a cycloalkyl-alkynyl-group in which the cycloalkyl and alkynyl moieties are as previously described.
xe2x80x9cCycloalkylenexe2x80x9d means a bivalent radical derived from a cycloalkyl group. Exemplary cycloalkylene radicals include cyclopentylene and cyclohexylene.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-COxe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaryl moiety are as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolnyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
xe2x80x9cHeteroarylalkenylxe2x80x9d means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl moieties are as previously described.
xe2x80x9cHeteroarylalkynylxe2x80x9d means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl moieties are as previously described.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroaryldiylxe2x80x9d means a bivalent radical derived from a heteroaryl group.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more beteroatoms selected from O, S or NY3 and optionally substituted by oxo; (ii) an partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring), each optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d, and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl-group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkylenexe2x80x9d means a bivalent radical derived from a heterocycloalkyl group.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain C1-4alkyl for example hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cPhenylenexe2x80x9d means an optionally substituted bivalent radical derived from a phenyl group. Suitable substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, particularly halogen, methyl or methoxy.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent a group R5Z1xe2x80x94Hetxe2x80x94 in which R5 is optionally substituted aryl (especially optionally substituted phenyl), optionally substituted heteroaryl, arylalkyl (e.g. benzyl and phenethyl) or cycloalkyl (e.g. cyclohexyl), Z1 is NH and Het is an 8 to 10 membered bicyclic system 
wherein ring 
is a 5 or 6 membered heteroaryl ring and ring 
is a 5 or 6 membered heteroaryl or a benzene ring, each ring optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, and the two rings are joined together by a carbonxe2x80x94carbon linkage or a carbon-nitrogen linkage.
Ring 
may particularly represent a 5 membered heteroaryl ring (especially a 5 membered azaheteroaryl ring), optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
Ring 
may particularly represent a benzene ring, optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. 
may particularly represent a 9 membered bicyclic system in which rings 
are as defined just above and the two rings are joined together by carbon atom linkages. 
is preferably optionally substituted benzoxazolyl or optionally substituted benzimidazolyl, each (more particularly ring 
optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), amino, halogen, hydroxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl].
R1 may also particularly represent a group R6N(R7)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar2xe2x80x94 in which R6 is C1-4alkyl (e.g. methyl or ethyl, especially methyl), R7 is aryl (especially an optionally substituted phenyl, where the optional substituent is an xe2x80x9caryl group substituentxe2x80x9d as defined above) and Ar2 is (i) optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4 alkyl, C1-4 alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) or (ii) optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4 alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group. Ar2 is preferably optionally substituted phenylene (e.g. p-phenylene), especially where the substituent is C1-4 alkyl or C1-4 alkoxy.
R1 may also particularly represent a group R6N(R7)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar2xe2x80x94 in which R6 is C1-4alkyl (e.g. methyl or ethyl, especially methyl), R7 is arylalkyl, especially aryl-CH2xe2x80x94 or aryl-CH(CH3)xe2x80x94, preferably optionally substituted benzyl or optionally substituted 1-phenylethyl, where the optional substituent is an xe2x80x9caryl group substituentxe2x80x9d as defined above and Ar2 is (i) optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) or (ii) optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group.
R1 may also particularly represent a group R6N(R7)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar2xe2x80x94 in which R6N(R7)xe2x80x94 is a bicyclic amine containing 9-10 atoms, especially indolinyl or tetrahydroquinolinyl and Ar2 is (i) optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) or (ii) optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group.
R1 may also particularly represent a group R6N(R7)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar2xe2x80x94 in which R6 is hydrogen, R7 is (i) aryl, especially optionally substituted phenyl, where the optional substituent is an xe2x80x9caryl group substituentxe2x80x9d as defined above or (ii) optionally substituted pyridyl, especially optionally substituted 2-pyridyl (preferred optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy) and Ar2 is (i) optionally substituted phenylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) or (ii) optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group. R7 is particularly phenyl or ortho substituted phenyl [preferred substituents include C1-4alkoxy (e.g. methoxy) or especially C1-4alkyl (e.g. methyl)]. Ar2 is preferably optionally substituted phenylene (e.g. p-phenylene), especially where the substituent is C1-4alkyl or C1-4alkoxy.
L1 may particularly represent a xe2x80x94R12xe2x80x94R13xe2x80x94 linkage where R12 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain (e.g. methylene), and R13 represents xe2x80x94C(xe2x95x90Z3)xe2x80x94NR11xe2x80x94, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NR11xe2x80x94, especially where R11 is hydrogen or lower alkyl (e.g. methyl).
Ar1 may particularly represent optionally substituted aryldiyl, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Ar1 may also particularly represent optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, more especially optionally substituted p-pyridinediyl. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Ar1 is preferably unsubstituted p-phenylene.
One of A1, A2 and A3 may particularly represent NR2 (especially wherein R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 or arylC1-4alkyl, e.g. benzyl) and the others represent CH2. R8 may preferably represent C1-4alkyl or phenyl.
Y may particularly represent carboxy.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which A1, A2, A3, R12, Ar1 and Y are as hereinbefore defined, R15 is hydrogen, halogen, lower alkyl or lower alkoxy, X1 is CR16 (where R16 is hydrogen, lower alkyl or lower alkoxy), X2 and X3 independently represent N or CR17 (where R17 is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl), and the group containing R12 is attached at the ring 3 or 4 position, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ia) and their prodrugs.
Compounds of formula (Ia) in which R15 represents hydrogen are preferred.
Compounds of formula (Ia) in which X1 represents CR16 where R16 is C1-4alkyl (e.g. methyl) are preferred.
Compounds of formula (Ia) in which X2 represents CR17, especially where R17 is C1-4alkoxy (e.g. methoxy) are also preferred.
Compounds of formula (Ia) in which X3 represents CH are also preferred.
Compounds of formula (Ia) in which R12 represents a straight or branched C1-6alkylene chain, especially a straight C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ia) in which Ar1 represents an optionally substituted aryldiyl, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ia) in which Ar1 represents optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, more especially optionally substituted p-pyridinediyl are also preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ia) in which Ar1 represents unsubstituted p-phenylene are particularly preferred.
Compounds of formula (Ia) in which one of A1, A2 and A3 represents NR2 [especially where R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 or arylC1-4alkyl] and the others represent CH2 are preferred.
Compounds of formula (Ia) in which Y represents carboxy are preferred.
The group containing R12 may preferably be attached at the ring 4 position.
A preferred group of compounds of the invention are compounds of formula (Ia) in which:
R15 is hydrogen; X1 represents CR16 (especially where R16 is C1-4alkyl, e.g. methyl); X2 represent CR17 (especially where R17 is C1-4alkoxy, e.g. methoxy); X3 represents CH; R12 is a straight C1-4alkylene chain (especially methylene); Ar1 is an optionally substituted phenylene (e.g. methyl or methoxy substituted p-phenylene, or especially unsubstituted p-phenylene,); one of A1, A2 and A3 represents NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 where R8 is C1-4alkyl or phenyl, or R2 is arylC1-4alkyl, e.g. benzyl) and the others represent CH2; Y represents carboxy; and the group containing R12 is attached at the ring 4 position; and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Another particular group of compounds of the invention are compounds of formula (Ib): 
in which R11, R12, Ar1, Ar2, A1, A2, A3 and Y are as hereinbefore defined, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ib) and their prodrugs.
Compounds of formula (Ib) in which Ar2 represents optionally substituted aryldiyl, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) are preferred.
Compounds of formula (Ib) in which Ar2 represents optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group. are also preferred.
Compounds of formula (Ib) in which R12 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ib) in which R11 represents hydrogen are preferred.
Compounds of formula (Ib) in which R11 represents lower alkyl (e.g. methyl) are also preferred.
Compounds of formula (Ib) in which Ar1 represents an optionally substituted aryldiyl, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar1 include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ib) in which Ar1 represents optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, more especially optionally substituted p-pyridinediyl are also preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ib) in which one of A1, A2 and A3 represents NR2 (especially wherein R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 or arylC1-4alkyl) and the others represent CH2 are preferred.
Compounds of formula (Ib) in which Y represents carboxy are preferred.
A preferred group of compounds of the invention are compounds of formula (Ib) in which:
Ar2 is p-phenylene or substituted p-phenylene (especially 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or p-pyridinediyl or substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; R12 is a straight or branched C1-4alkylene chain, (especially methylene); R11 is hydrogen or lower alkyl (e.g. methyl); Ar1 is an optionally substituted aryldiyl [especially p-phenylene, and methyl(or methoxy) substituted p-phenylene]; one of A1, A2 and A3 represents NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 where R8 is C1-4alkyl or phenyl, or R2 is arylC1-4alkyl, e.g. benzyl) and the others represent CH2; Y represents carboxy; and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Another particular group of compounds of the invention are compounds of formula (Ic): 
in which R11, R12, Ar1, Ar2, A1, A2, A3 and Y are as hereinbefore defined, R6 is lower alkyl, R18 is hydrogen or methyl, Ar3 is aryl and m is zero or 1, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ic) and their prodrugs.
Compounds of formula (Ic) in which Ar3 represents phenyl, optionally substituted by an xe2x80x9caryl group substituentxe2x80x9d as defined above, are preferred.
Compounds of formula (Ic) in which R6 represents C1-4alkyl, especially methyl or ethyl, are preferred.
Compounds of formula (Ic) in which Ar2 represents optionally substituted aryldiyl, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulphinyl and C1-4alkylsulphonyl, especially methyl, methoxy, methylthio, methylsulphinyl and methylsulphonyl) are preferred.
Compounds of formula (Ic) in which Ar2 represents optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optional substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group. are also preferred.
Compounds of formula (Ic) in which R12 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ic) in which R11 represents hydrogen are preferred.
Compounds of formula (Ic) in which R11 represents lower alkyl (e.g. methyl) are also preferred.
Compounds of formula (Ic) in which Ar1 represents an optionally substituted aryldiyl, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar1 include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ic) in which Ar1 represents optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, more especially optionally substituted p-pyridinediyl are also preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ic) in which one of A1, A2 and A3 represents NR2 (especially wherein R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 or arylC1-4alkyl) and the others represent CH2, are preferred.
Compounds of formula (Ic) in which Y represents carboxy are preferred.
A preferred group of compounds of the invention are compounds of formula (Ic) in which:
Ar3 is phenyl; R18 is hydrogen or methyl; m is zero or one; R6 is C1-4alkyl (especially methyl or ethyl); Ar2 is p-phenylene or optionally substituted p-phenylene (especially 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or p-pyridinediyl or substituted p-pyridinediyl [especially 4(or 6)-methyl(or methoxy)-p-pyridine-2,5-diyl]; R12 is a straight or branched C1-4alkylene chain, (especially methylene); R11 is hydrogen or lower alkyl (e.g. methyl); Ar1 is an optionally substituted phenylene [especially p-phenylene, and methyl(or methoxy) substituted p-phenylene]; one of A1, A2 and A3 represents NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 where R8 is C1-4alkyl or phenyl, or R2 is arylC1-4alkyl, e.g. benzyl) and the others represent CH2; Y is carboxy; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another particular group of compounds of the invention are compounds of formula (Id): 
in which R5, R12, Ar1, A1, A2, A3 and Y are as hereinbefore defined, X is NR or O (where R is H or lower alkyl), R19 is hydrogen, C1-4alkyl or C1-4alkoxy, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Id) and their prodrugs.
Compounds of formula (Id) in which R5 represents optionally substituted aryl, especially optionally substituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkyl (e.g. methoxy), halo (e.g. fluoro) and Y1Y2Nxe2x80x94 (e.g. dimethylamino). R5 especially represents ortho-tolyl.
Compounds of formula (Id) in which R12 represents a straight or branched C1-6alkylene chain, especially a straight C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Id) in which Ar1 represents an optionally substituted aryldiyl, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar1 include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Id) in which Ar1 represents optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, more especially optionally substituted p-pyridinediyl are also preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Id) in which Ar1 represents unsubstituted p-phenylene are particularly preferred.
Compounds of formula (Id) in which one of A1, A2 and A3 represents NR2 (especially wherein R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 or arylC1-4alkyl) and the others represent CH2 are preferred.
Compounds of formula (Id) in which Y represents carboxy are preferred.
A preferred group of compounds of the invention are compounds of formula (Id) in which:
R5 is optionally substituted phenyl (especially ortho-tolyl); X is O; R12 is a straight C1-4alkylene chain (especially methylene); Ar1 is an optionally substituted phenylene (e.g. methyl or methoxy substituted p-phenylene, or especially unsubstituted p-phenylene); one of A1, A2 and A3 represents NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8 where R8 is C1-4alkyl or phenyl, or R2 is arylC1-4alkyl, e.g. benzyl) and the others represent CH2; Y is carboxy; and the group containing R12 is attached at the benzoxazole ring 6 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Particular compounds of the invention are selected from the following:
1-benzyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-2-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-(3-carboxy-propionyl)4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-2-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-isoxazole-3-carbonyl)-4-(4-{2-[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-(methyl-{[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-(methyl-{[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-isoxazole-3-carbonyl)4-{4-[methyl-({4-[3-methyl-3-(2-methyl-hexa-1,3,5-trienyl)-ureido]-phenyl}-acetyl)-amino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetylamino)-phenyl]-1-(5-methyl-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(5-methyl-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-1-(5-methyl-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[3-methoxy-4-(3-methyl-3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-1-(thiophene-2-carbonyl)-pyirolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-1-(5-methyl-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-{4-[({4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetyl)-methyl-amino]-phenyl}-(5-methyl-isoxazole-3-carbonyl)-pyrolidine-3-carboxylic acid;
1-acetyl-4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-(thiophene-2-carbonyl)4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-(pyridine-4-carbonyl)4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-(morpholin-4-yl-acetyl)-4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-4-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-4-(4-{methyl-[(2-o-tolylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamnino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrolidine-3-carboxylic acid;
4-[4-({[2-(2-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-ethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(2-chloro-phenylaminno)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-ammo)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2,6-dimethyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyirolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-cyano-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(3-methoxy-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
1-(morpholin-4-yl-acetyl)4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)4-{4-[2-(2-phenylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4(4{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)4-(4-{methyl-[(2-phenylamino-benzoxazol-6-yl)-acetyl]-amino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
1-(pyridine-4-carbonyl)4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-(morpholin-4-yl-acetyl)4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-4-(4-{2-[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-4-[4-(methyl-{[2-(pyridin-3-ylamino)-benzoxazol-6-yl]-acetyl}-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-(4-{2-[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetylamino}-phenyl)-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
1-benzoyl-4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(thiophene-2-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(pyridine-4-carbonyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(morpholin-4-yl-acetyl)-pyrrolidine-3-carboxylic acid;
4-[4-({[2-(2-chloro-6-methyl-phenylamino)-benzoxazol-6-yl]-acetyl}-methyl-amino)-phenyl]-1-(5-methyl-2,5-dihydro-isoxazole-3-carbonyl)-pyrrolidine-3-carboxylic acid;
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Preferred compounds of the invention are:
1-benzoyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-acetyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
1-(3-carboxy-propionyl)4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid;
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of xcex14xcex21 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler. Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to 15;t obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined, and Y is carboxy may be prepared by hydrolysis of esters of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined and where the Y is a xe2x80x94CO2R20 group (in which R20 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined, and Y is carboxy may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined and Y is a xe2x80x94CO2R20 group (in which R20 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
As another example compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined and Y is carboxy may be prepared by hydrogenation of compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined and Y is a xe2x80x94CO2R20 group (in which R20 is benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
In a process A compounds of formula (I), containing an amide bond may be prepared by coupling of an acid (or an acid halide) with an amine to give an amide bond using standard peptide coupling procedures as described hereinafter.
As an example of process A, compounds of formula (I) wherein R1, Ar1, A1, A2 and A3 are as hereinbefore defined, L1 is xe2x80x94R12xe2x80x94R13xe2x80x94 (in which R12 is as hereinbefore defined and R13 is xe2x80x94C(xe2x95x90O)xe2x80x94NR11xe2x80x94) and Y is a xe2x80x94CO2R20 group (in which R20 is as hereinbefore defined) may be prepared by reaction of compounds of formula (II): 
wherein R11, R20, Ar1, A1, A2 and A3 are as hereinbefore defined with compounds of formula (III):
R1xe2x80x94R12xe2x80x94C(xe2x95x90O)xe2x80x94X4xe2x80x83xe2x80x83(III) 
wherein R1 and R12 are as hereinbefore defined, and X4 is a hydroxy group or a halogen, preferably chlorine, atom. When X4 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures for example coupling in the presence of benzotriazol-1lyloxytris(dimethylamino)phosphonium hexafluorophosphate and triethylamine (or diisopropylethylamine) and dimethylaminopyridine in tetrahydrofuran (or dimethylformamide), at room temperature. When X4 is a halogen atom the acylation reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
As another example of process A, compounds of formula (I) wherein R1, L1, Ar1 are as hereinbefore defined, Y is carboxy and one of A1, A2 and A3 is NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8) whilst the others represent C(R3)(R4) may be prepared by reaction of compounds of formula (IV): 
wherein R1, L1 and Ar1 are as hereinbefore defined, Y is carboxy and one of A1, A2 and A3 is NH and the others represent C(R3)(R4) with compounds of formula (V):
R8xe2x80x94C(xe2x95x90O)xe2x80x94X5xe2x80x83xe2x80x83(V) 
wherein R8 is as defined hereinbefore and X5 is a halogen, preferably chlorine, atom. The acylation reaction may conveniently be carried out using standard reaction conditions for example those described hereinbefore.
Esters of formula (I) wherein R1, L1, Ar1 are as hereinbefore defined, Y is a xe2x80x94CO2R20 group (in which R20 is as hereinbefore defined) and one of A1, A2 and A3 is NR2 (in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8) whilst the others represent C(R3)(R4) may be similarly prepared by reaction of compounds of formula (IV) wherein R1, L1 and Ar1 are as hereinbefore defined, Y is a xe2x80x94CO2R20 group (in which R20 is as hereinbefore defined) and one of A1, A2 and A3 is NH whilst the others represent C(R3)(R4) with compounds of formula (V) wherein R8 is as defined hereinbefore and X5 is a hydroxy group or a halogen, preferably chlorine, atom, using standard reaction conditions for example those described hereinbefore.
According to a further feature of the present invention, compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined, and Y is xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, may be prepared by reaction of compounds of formula (I) wherein R1, L1, Ar1, A1, A2 and A3 are as hereinbefore defined, and Y is carboxy, with hydroxylamine using standard peptide coupling procedures such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran and at a temperature at about room temperature. The coupling may also be carried out using 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dichloromethane at room temperature. The preparation may also be carried out using an O-protected hydroxylamine such as O-(trimethylsilyl)hydroxylamine, O-(t-butyldimethylsilyl)-hydroxylamine, or O-(tetrahydropyranyl)hydroxylamine followed by treatment with acid.
As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90xc2x0 C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60xc2x0 C.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates. As an example compounds of formula (I) wherein Y is carboxy may coupled with camphor sultame, followed by separation of the diastereoisomers and then regeneration of the individual isomers of compounds of formula (I) by treatment with aqueous sodium hydroxide solution, in methanol, at a temperature at about room temperature.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Compounds of formula (II) wherein R20, Ar1, A1, A2 and A3 are as hereinbefore defined and R11 is hydrogen, may be prepared by reduction of the corresponding nitro compounds of formula (1): 
wherein R20, Ar1, A1, A2 and A3 are as hereinbefore defined. The reduction may conveniently be carried out using standard methods for the reduction of aromatic nitro compounds to the corresponding aromatic amines, for example (i) treatment with tin chloride in an inert solvent, such as ethyl acetate or dimethylformamide, at a temperature at about 70xc2x0 C., (ii) treatment with tin in the presence of hydrochloric acid in ethanol at a temperature at about reflux temperature or (iii) hydrogenation in the presence of palladium on carbon.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NR2 [in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94R8] and the others represent C(R3)(R4), may be prepared by reaction compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NH and the others represent C(R3)(R4), with compounds of formula (2):
R8xe2x80x94C(xe2x95x90O)xe2x80x94X6xe2x80x83xe2x80x83(2) 
wherein R8 is as hereinbefore defined and X6 is a hydroxy group or a halogen, preferably chlorine, atom. The reaction may be carried out by standard peptide coupling or acylation procedures for example those described hereinbefore.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NR2 [in which R2 is xe2x80x94C(xe2x95x90O)xe2x80x94OR8a] and the others represent C(R3)(R4), may be prepared by reaction compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NH and the others represent C(R3)(R4), with compounds of formula (3):
R8aOxe2x80x94C(xe2x95x90O)xe2x80x94Clxe2x80x83xe2x80x83(3) 
wherein R8a is as hereinbefore defined. The reaction may be carried out by standard acylation procedures for example those described hereinbefore.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NR2 [in which R2 is R8b] and the others represent C(R3)(R4), may be prepared by reaction compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NH and the others represent C(R3)(R4), with compounds of formula (4):
R8bxe2x80x94X7xe2x80x83xe2x80x83(4) 
wherein R8b is as hereinbefore defined and X7 is a hydroxy group or a halogen, preferably chlorine, atom The reaction may be carried out by standard alkylation procedures for example those described hereinbefore.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents NH and the others represent C(R3)(R4), may be prepared by reaction of compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents Nxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CHxe2x95x90CH2 and the others represent C(R3)(R4), with a mineral acid, such as hydrochloric acid, in an inert solvent, such as dioxane and at a temperature at about room temperature.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents Nxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CHxe2x95x90CH2 and the others represent C(R3)(R4), may be prepared by reaction of compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, one A1, A2 and A3 represents Nxe2x80x94CH2Ph and the others represent C(R3)(R4), with vinyl chloroformate at reflux temperature.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, A1 and A3 represent CH2, A2 represents Nxe2x80x94CH2Ph, may be prepared by reaction of compounds of formula (5):
O2Nxe2x80x94Ar1xe2x80x94CHxe2x95x90CHxe2x80x94CO2R20xe2x80x83xe2x80x83(5) 
wherein R20 and Ar1 are as hereinbefore defined, with N-(butoxymethyl)-N-(trimethylsilylmethyl)benzylamine in the presence of trifluoroacetic acid and at a temperature at about room temperature.
Compounds of formula (1) wherein R20 and Ar1 are as hereinbefore defined, A2 and A3 represent CH2 and A1 represents Nxe2x80x94C(xe2x95x90O)xe2x80x94R8, may be prepared by reaction of compounds of formula (6):
O2Nxe2x80x94Ar1xe2x80x94CHxe2x95x90Nxe2x80x94CH2SiMe3xe2x80x83xe2x80x83(6) 
wherein Ar1 is as hereinbefore defined, with an acrylate ester of formula (7):
CH2xe2x95x90CHxe2x80x94CO2R20xe2x80x83xe2x80x83(7) 
wherein R20 is as hereinbefore defined, and an acid chloride of formula (2) wherein R8 and X6 are as hereinbefore defined, in an inert solvent, such as tetrahydrofuran, and at a temperature at about reflux temperature.
Compounds of formula (6) wherein Ar1 is as hereinbefore defined may be prepared by the application or adaptation of the methods of K. Achiwa et al, Chem. Pharm. Bull., 1983, 31, page 3939.
Compounds of formula (IV) wherein R1, L1 and Ar1 are as hereinbefore defined, Y is carboxy and one of A1, A2 and A3 is NH whilst the others represent C(R3)(R4) may be prepared by hydrogenation of compounds of formula (I) wherein R1, L1 and Ar1 are as hereinbefore defined, Y is carboxy and one of A1, A2 and A3 is NCH2Ph whilst the others represent C(R3)(R4). The hydrogenation may conveniently be carried out in the presence of palladium hydroxide in acetic acid under pressure and at a temperature at about room temperature.
Intermediates of formulae (II), (IV) and (1) are novel compounds and, as such, they and their processes described herein for their preparation constitute further features of the present invention.
Intermediates of formulae (IV) are also able to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
1H spectra NMR at 600 MHz were recorded on DMX 600 Bruker. 1H spectra NMR at 500 MHz were recorded on DRX 500 Bruker. 1H spectra NMR at 400 MHz were recorded on DRX 400 Bruker. 1H spectra NMR at 300 MHz were recorded on AC 300 Bruker. 1H spectra NMR at 250 MHz were recorded on AC 250 Bruker. b=broad signal, bd=broad doublet, bs=broad singlet, bt=broad triplet, d=doublet, dd=double doublet, m=multiplet, s=singlet, t=triplet, 2bs=two broad singlets, 2d=two doublets, 2m =two multiplets, 2s=two singlets,
Desorption Chemical Ionization Mass Spectra, MS (DCI), were recorded on a Finnigan SSQ 7000 spectrometer using ammonia as the reactant gas.
Electron Impact Mass Spectra, MS (EI), were recorded on a Finnigan SSQ 7000 spectrometer at 70eV.
Fast Atom Bombardment Mass Spectra, MS(FAB), were recorded on an Autospec micromass.
Liquid Secondary Ion Mass Spectra, MS(LSIMS), were recorded on a VG AutoSpec spectrometer using a mixture of glycerol-thioglycerol {fraction (50/50)} as the matrix.